Journal of Cerebral Blood Flow & Metabolism

Obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease, but acute intracranial dynamics during obstructive events remain uncertain. We hypothesized that negative intrathoracic pressure elevates intracranial pressure (ICP) by increasing central venous pressure (CVP) and impairing cerebral venous outflow. In an anesthetized porcine model, we measured ICP during simulated OSA with intermittent negative airway pressure (INAP) or positive end-expiratory pressure (PEEP) under controlled blood gas conditions. INAP consistently produced post-apneic ICP surges (+10 mmHg) that were time-locked to CVP spikes with strong ICP–CVP coupling during INAP (r = 0.74) and moderate pooled correlation across all epochs (r = 0.48). Pooled associations with arterial blood pressure (r = −0.02) and cerebral blood flow (r = 0.24) were negligible. The magnitude of responses was modulated by blood gases: hyperoxia attenuated ICP/CVP changes, whereas hypercapnia augmented pressure surges and was associated with modest changes in global cerebral blood flow without proportionally increasing peak ICP. PEEP was accompanied by immediate increase in ICP and CVP, consistent with direct pressure transmission to the venous system. Collectively, these findings support a venous-mechanical contribution as a key driver of acute ICP elevation during obstructive events, with chemoregulatory effects modulating the response, and provide a hemodynamic context for OSA’s established cerebrovascular risk associations.

Neonatal hypoxic–ischemic encephalopathy (HIE) is a leading cause of infant mortality and long-term neurological disability. Current treatments offer limited efficacy, especially in premature or severely affected infants. The pathology of HIE involves a cascade of cellular damage initiated by oxygen and nutrient deprivation, followed by reperfusion injury characterized by excessive reactive oxygen species (ROS) production and mitochondrial dysfunction. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a critical role in maintaining mitochondrial integrity, dynamics, and quality control through mitophagy and programmed cell death. In this study, we examined changes in CL subspecies in an in vitro ischemia/reperfusion model and small and large animal models of neonatal HIE. We observed a significant increase in the ratio of monolysocardiolipin (MLCL) to CL and significant increase in saturated CL species following injury. Genetic ablation of Tafazzin protein using conditional Taz knockout mice resulted in accumulation of MLCL and demonstrated larger brain infarct size following HIE in mice, but without affecting mitochondrial respiration or mitochondrial dynamics under basal conditions. These findings suggest that CL remodeling and MLCL accumulation contribute to the progression of neonatal HIE pathology. This study highlights an underexplored mechanism linking cardiolipin remodeling to brain injury severity, offering potential therapeutic targets for neonatal HIE.

Many infants with mild hypoxic–ischemic encephalopathy (HIE) are treated with therapeutic hypothermia despite the lack of robust preclinical and clinical data that hypothermia is safe and effective. The aim of this study was to determine if hypothermia is neuroprotective after mild hypoxia–ischemia (HI). Chronically instrumented near-term fetal sheep (0.85 gestation) were randomized to sham control (n = 8) or to HI induced by 10 min of bilateral carotid artery occlusion followed by normothermia (HI-normothermia, n = 8) or 72 h of hypothermia started 6 h after the end of HI (HI-hypothermia, n = 8) and recovered for 7 days. Mild HI was associated with reduced electroencephalographic power compared with sham controls until 78 h after HI. HI was associated with a loss of neurons and an increase in microglia within the hippocampus, while HI-hypothermia restored numbers of neurons and microglia back to sham control. There was no difference in the number of total oligodendrocytes between groups. HI-hypothermia was associated with a significant decrease in mature oligodendrocyte number and myelin basic protein area fraction compared with sham control, despite no change in HI-normothermia. Hypothermia for 72 h is significantly neuroprotective within the hippocampus but potentially delays white matter maturation when started 6 h after mild HI.

This cohort study was conducted using prospective and retrospective data to investigate whether indirect encephaloduroarteriosynangiosis (EDAS) revascularization can reduce the risk of rebleeding in adult patients with hemorrhagic moyamoya disease (hMMD). We enrolled adult patients diagnosed with hMMD prospectively and retrospectively. All patients voluntarily chose to undergo EDAS or conservative treatment. The clinical features, angiographic findings, and follow-up outcomes were investigated and analyzed using the Kaplan–Meier survival analysis and Cox proportional hazards regression models to estimate rebleeding risks post-EDAS. Among the 186 patients with hMMD, 123 patients (66.1%) underwent EDAS, and 63 patients (33.9%) received conservative treatment. In the EDAS group, one (0.8%) patient suffered postoperative infarction, 16 patients (13.0%) experienced recurrent cerebral hemorrhage, and three patients (2.4%) died from rebleeding events. In the conservative treatment group, 18 patients (28.6%, p = 0.015) experienced cerebral rebleeding events and seven (11.1%, p = 0.033) died from rebleeding events. According to the Kaplan–Meier analysis, the annual rebleeding incidence rate was 1.4%/year in the EDAS group and 3.6%/year in the conservative treatment group (p = 0.005, Log-Rank test). Multivariate Cox regression analysis revealed that EDAS surgery was a protective predictor for rebleeding events, while age and the dilation of posterior choroidal artery were positive factors influencing recurrent hemorrhage events. Long-term follow-up results show that, compared to conservative treatment, EDAS revascularization can effectively reduce the rate of recurrent cerebral hemorrhage in adult patients with hMMD.

The NeuroEXPLORER (NX), a next generation brain-dedicated PET scanner, has demonstrated improved spatial resolution and sensitivity compared with previous PET scanners. In this study, we performed synaptic vesicle glycoprotein 2A (SV2A) PET, an in vivo marker of synaptic density, to evaluate the performance of the NX in both fetal and maternal brains of four pregnant rhesus macaques. Results were compared with the previously acquired PET images using miniEXPLORER and Biograph mCT for fetal and maternal brains (four pregnant monkeys per scanner). The NX demonstrated superior performance compared with the other scanners, providing improved image clarity and higher distribution volume ratios (DVRs), which were significant in the occipital region and putamen of the fetal brain (p < 0.05, FDR uncorrected), as well as across all regions in the maternal brain (p < 0.05, FDR corrected). The percentage difference in mean regional DVR between maternal and fetal brains ranged from 36.1% in the amygdala to 78.3% in the occipital lobe in the NX, which may reflect regional differences in the phase of synaptic development. This study highlights the NX as a promising non-invasive tool for investigating in utero synaptic development. The presence of in utero motion emphasizes the necessity of motion correction for reliable PET quantification.

Synaptic vesicle glycoprotein 2A (SV2A) PET imaging enables the estimation of synaptic density in the brain. The most widely used SV2A tracer, ¹¹C-UCB-J, shows age-related effects in healthy volunteers (HV) and its short radioactive half-life limits clinical applicability. ¹⁸F-SynVesT-1 has a longer half-life, but its quantification and dependence on age/sex need further validation. In this study, 40 HV aged 24–85 (21F/19M) underwent 90-min ¹⁸F-SynVesT-1 PET–MR with arterial sampling. Distribution volumes (V_T) and distribution volume ratios (DVR) were estimated using one-tissue (1TC) and two-tissue (2TC) compartment models, and Logan graphical analysis (LGA). 1TC and LGA showed strong agreement with 2TC V_T (R² ⩾ 0.97). Standardised uptake value ratios (SUVR) were evaluated across different time windows, using the centrum semiovale (CSO) and cerebellar (pseudo-)reference regions. SUVR_CSO 60–90 min correlated best with DVR_CSO. The thalamus and cingulate cortex showed age-related decreases in ¹⁸F-SynVesT-1 DVR_CSO (~2%/decade). Ten subjects (52 ± 21 years; 5F/5M) also underwent ¹¹C-UCB-J PET for a head-to-head comparison. ¹⁸F-SynVesT-1 showed lower cortical V_T (−7% ± 9%) but higher DVR_CSO (37% ± 4%). This study shows that ¹⁸F-SynVesT-1 can be reliably quantified by SUVR in healthy volunteers, and correlates well with ¹¹C-UCB-J. These findings support the broader application of ¹⁸F-SynVesT-1. This study was registered on clinicaltrial.gov (NCT05384353).

Quantitative susceptibility mapping (QSM) enables non-invasive assessment of brain iron dysregulation following ischemic injury. We conducted a systematic review to evaluate the role of QSM-derived susceptibility in deep gray matter (DGM) nuclei after ischemic cerebrovascular events (iCVEs). Included studies had to enroll patients with iCVEs who underwent QSM and provide findings of DGM susceptibility. Finally, 11 studies were identified, providing data on hemispheric differences, comparisons with healthy controls, clinical correlates, prognostic value, and longitudinal changes. Meta-analyses were performed on hemispheric differences and demonstrated higher susceptibility in the ipsilateral basal ganglia compared with the contralateral hemisphere. Increased susceptibility was consistently observed in the putamen when compared with healthy controls. Limited cross-sectional evidence suggested positive associations between DGM susceptibility and neurological or functional deficits. Longitudinal findings were scarce and based on small cohorts. However, population homogeneity was evident across studies, mainly due to the predominance of Chinese cohorts, alongside substantial heterogeneity in patient characteristics and methodologies. Overall, current evidence preliminarily suggests increased iron deposition in the basal ganglia after iCVEs, particularly the putamen. Standardized longitudinal studies in geographically diverse populations are needed to strengthen the reliability and cross-study reproducibility of findings and to better clarify their clinical relevance.

Previously, water exchange across the blood–brain barrier (BBB) and blood–cerebrospinal barrier (BCSFB) was assessed by multi-delay, multi-echotime (TE) arterial spin labeling, albeit in separate acquisitions with different settings. In this study, we present a protocol for simultaneous measurement of BBB and BCSFB water exchange using a multi-TE 3D-GRASE acquisition combined with T₂-preparation. We evaluate several modeling approaches, comparing two- and three-compartment models to estimate water exchange rates from blood to gray matter (K_{bl → GM}), and to CSF (K_{bl → CSF}). ASL signal was consistent with expectations: at early time points, signal decayed rapidly across TEs in blood and GM, whereas at later time points decay was slower, consistent with label accumulation in CSF. All models yielded CBF and ATT values consistent with literature. K_{bl → CSF} was highest in the choroid plexus (≈1.75 × 10⁻² s^–1), with lower values in GM and subarachnoid space (≈1.4 × 10⁻² s^–1), and white matter (≈1.2 × 10⁻² s^–1) ROIs. In contrast, K_{bl → GM} was homogenous across the brain. The three-compartment model yielded similar Akaike Information Criterion values to the two-compartment model, but allows more insight into physiology and is thus preferred. Overall, the protocol allowed simultaneous characterization of BBB and BCSFB dynamics, with the three-compartment model offering the most informative representation of water exchange.

Recent advances in functional PET (fPET) enable modeling of metabolic processes with second-level temporal resolution, opening applications such as imaging molecular connectivity comparable to fMRI. However, high-temporal fPET is more noise-sensitive, making meaningful signal extraction challenging. We developed a component-based preprocessing method adapted from fMRI, which models structured noise with tissue-specific regressors and removes low-frequency uptake trends (CompCor). This approach was applied to 20 high-temporal [¹⁸F]FDG–fPET scans from a long-axial PET/CT system (1 s frames) and 16 scans from a PET/MR scanner (3 s frames). Filtering methods were compared across frequency bands, and their effects on metabolic connectivity (M-MC) assessed. Connectivity was strongly influenced by filter strategy and scanner type. CompCor produced more consistent, structured networks than standard bandpass filters. Intermediate frequency bands (0.01–0.1 Hz) gave the most reliable connectivity across PET/CT and PET/MR (r = 0.89), while high-sensitivity PET/CT also revealed structured patterns at 0.1–0.2 Hz. Compared to fMRI, fPET networks appeared more spatially cohesive but less differentiated. In sum, high-temporal [¹⁸F]FDG–fPET enables high within-scan reliability estimation of resting-state M-MC when paired with appropriate denoising, opening a new avenue in molecular imaging. Scanner characteristics and preprocessing critically affect signal quality, while our physiologically informed pipeline improves comparability across systems and studies.

Ischemic stroke, intracerebral hemorrhage (ICH), aneurysmal subarachnoid hemorrhage (aSAH), global hypoxic ischemic brain injury following cardiac arrest (HIBI), and traumatic brain injury (TBI) present clinical pathologies that share brain ischemia as a primary or secondary consequence of their respective pathophysiology. Recently, sex—as a biological variable—has received attention for its clear implications in differences in injury pathophysiology, diagnosis, and management. Due to historical, social, and gender biases, females have been excluded from physiology-based research and clinical trials, resulting in limited insight into female physiology and poor translation of current diagnostics and therapies to females. The role of sex-specific hormones has been implicated in a host of sex differences following cerebrovascular injury and the ensuing clinical outcomes. Therefore, this review aims to provide a contemporary overview on the role of biological sex and sex hormones in the underlying physiology, mechanisms, and outcomes of selected cerebrovascular injuries. First, we identify sex-based differences in clinical outcomes in ischemic stroke, ICH, aSAH, HIBI, and TBI. Second, we discuss the impact of biological sex and sex hormones on the fundamentals of cerebrovascular physiology. Finally, related mechanisms of sex-based differences in injury pathophysiology are explored to identify potential therapeutic avenues for future research.

Whether endovascular thrombectomy (EVT) benefits medium vessel occlusion (MeVO) stroke remains uncertain. Brain frailty, reflecting chronic small-vessel disease and neurodegeneration, may indicate weaken collateral circulation and limit tissue salvage. We retrospectively studied 227 MeVO patients who achieved successful reperfusion (mTICI 2b–3). Baseline multimodal CT (NCCT + CTP) and follow-up MRI/CT were used to quantify the penumbral salvage index (PSI). Brain frailty was categorized on NCCT as absent (n = 66), mild (n = 88), or moderate-to-severe (n = 73) based on white matter hyperintensities, atrophy, and vascular lesions. Mediation analysis tested the indirect effect through collateral status. Greater frailty severity was associated with progressively lower PSI (0.81 vs 0.70 vs 0.63, p < 0.001). In multivariable models, higher frailty independently predicted lower PSI (β = −0.19, p = 0.003). Collateral dysfunction mediated 38% of the frailty–PSI association. Correspondingly, rates of excellent outcome (mRS 0–1) and functional independence (mRS 0–2) at 90 days declined with increasing frailty severity (both p < 0.001). These findings identify brain frailty as an independent predictor of impaired penumbral salvage for MeVO after EVT and links it to worse 90-day outcomes. The effect appears substantially mediated by collateral failure. Incorporating brain frailty into acute assessment may improve prognostic stratification among patients who achieve successful reperfusion.

The lifetime accumulation of vascular risk factors shapes susceptibility to ischemic stroke but does not account for the striking divergence in tissue outcome following large artery occlusion, as some individuals experience infarction of variable severity while others remain neurologically intact. Although the classical core–penumbra framework captures general relationships between perfusion severity and tissue viability, it fails to explain this marked inter-individual heterogeneity under comparable ischemic stress. We recently established the nitric oxide synthase inhibitor-mediated large artery ischemic stroke model (NAIM), which converts unilateral carotid occlusion from a typically benign oligemic state into a high-incidence yet non-deterministic infarction paradigm. In this review, we present NAIM as a mechanistically defined platform for investigating infarction occurrence as a threshold-driven process spanning vascular, metabolic, and microcirculatory scales. Using a large-scale NAIM dataset (n = 900 mice) from our recent study, we reappraise the original findings and extend the analysis to post-hoc observations not addressed in the initial report. Finally, integrating these experimental insights with clinical and basic investigations from our group and the broader literature, we outline how ischemic outcome (tissue survival vs infarction) emerges from a threshold-sensitive nonlinear system defined by collateral anatomy; macro-/micro-vascular integrity; and systemic, metabolic, and genetic modifiers.

Vascular pulsations are increasingly recognized as key contributors to cerebral perfusion and brain clearance mechanisms, with alterations linked to aging and neurodegenerative diseases. However, capturing fast physiological dynamics in preclinical models remains technically challenging due to high cardiac frequencies and small brain size. Here, we investigated the feasibility of zero echo time (ZTE) functional MRI (fMRI) to capture cardiac- and respiration-related pulsations across multiple temporal scales in the rat brain under isoflurane anesthesia. We used retrospective binning to assess cardiac- and respiration-related pulsations. Cardiovascular state was modulated with medetomidine, and functional connectivity analyses were performed to evaluate slower neural dynamics. ZTE fMRI robustly detected physiological pulsations across the brain, achieving effective temporal resolution of 8 ms, with the strongest signals observed in large arteries, consistent with an inflow‑based contrast mechanism. Cardiac pulsation amplitudes increased significantly under combined medetomidine–isoflurane anesthesia, whereas respiration‑related pulsations remained stable. Functional connectivity decreased under combined anesthesia, confirming ZTE fMRI sensitivity to slower neural dynamics. ZTE fMRI enables simultaneous assessment of cerebrovascular pulsatility and functional connectivity, providing a powerful tool for studying physiological brain dynamics in vivo.

Cerebrovascular reactivity (CVR) is increasingly recognized as a valuable clinical biomarker, making accurate, and reliable quantification essential, particularly in the absence of a gold-standard reference. However, both the acquisition and processing of CVR data are influenced by numerous methodological factors, including imaging technique, sequence parameters, vascular paradigm, and data processing strategies. These complexities can be daunting for newcomers and hinder methodological consistency across studies. To support both novice and experienced researchers, we systematically evaluated how different processing strategies affect CVR map repeatability, quantified using spatial intraclass correlation, across multiple vascular paradigms. Twenty-four healthy volunteers underwent BOLD–CVR imaging using CO₂ inhalation, breath-hold, and resting-state paradigms, each repeated in a test–retest setup. We found that optimal processing choices varied across paradigms and interacted in non-trivial ways. For example, the inclusion of motion-confounds and the application of temporal filtering require careful consideration, as they can introduce substantial collinearity in the regression model and reduce repeatability. We summarized these findings into practical insights to guide researchers in making sound methodological choices and promote consistency within the field.

Deficits in the synaptic vesicle protein 2A (SV2A) have been reported in various neurodegenerative diseases including Alzheimer’s and Huntington’s disease (HD). SV2A levels can be investigated using positron emission tomography (PET) radioligands such as [¹¹C]UCB-J, [¹⁸F]UCB-J, and [¹⁸F]SynVesT-1. To compare the in vivo performance of the PET radioligands [¹⁸F]UCB-J and [¹⁸F]SynVesT-1 in terms of brain penetration, binding profile, and SV2A quantification, we here report a head-to-head study in a mouse model of HD. Dynamic µPET/CT scans (60 min) were acquired in 17-month-old heterozygous (HET, n = 20) zQ175DN and wild-type (WT, n = 19) mice. Brain time-activity curves and image-derived input function were extracted and kinetic modeling was performed using Logan and the two-tissue compartmental model (2TCM). Intra-animal comparison between both radioligands revealed significantly higher K₁ (p < 0.01) but equal k₂ for [¹⁸F]SynVesT-1 compared to [¹⁸F]UCB-J. V_T(IDIF) (Logan) quantification found significantly higher values for [¹⁸F]SynVesT-1 compared to [¹⁸F]UCB-J regardless of genotype (e.g. striatum WT: 22.4 ± 2.7 vs 18.6 ± 1.8 mL/cm³). Regional analyses comparing the average V_T(IDIF) between genotypes showed no significant differences; however, voxel-based V_T(IDIF) analyses revealed significant SV2A alterations in several subregions of the brain for both radioligands. Overall, [¹⁸F]SynVesT-1 and [¹⁸F]UCB-J showed agreement across analyses, demonstrating the equal applicability of both radioligands for SV2A PET imaging.

Molecular imaging of the interaction between astrocytes and neurons in humans is an important yet challenging task. While previous studies indicated that activation of astrocytes may contribute to the loss of neurons, the paper by Crine et al. in this issue found the opposite, a corresponding decline of imaging markers for astrocytes and dopaminergic neurons. This is a comment on the limitations and future perspectives for research on the interaction between glia and neuronal survival in aging and neurodegenerative diseases in humans.

Cerebral edema and neurovascular dysfunction are reliable predictors of outcome after acute ischemic stroke (AIS), yet effective targeted therapies remain limited. We investigated the therapeutic potential of trifluoperazine (TFP), an FDA-approved antipsychotic and calmodulin inhibitor that modulates astrocytic aquaporin-4 expression. TFP administered after recanalization in a mouse model of AIS reduced infarct volume and improved early neurological recovery. Importantly, TFP restored neurovascular coupling and enhanced cerebral blood flow responses to spreading depolarizations, indicating improved cerebrovascular function. Mechanistic studies in acute brain slice preparations demonstrated that TFP attenuates cytotoxic tissue swelling, suppresses spreading depolarizations, reduces aquaporin-4 expression and preserves neuronal integrity under osmotic stress. These findings suggest that transient modulation of astrocytic cytotoxic edema and vascular reactivity represents a viable strategy to improve early stroke outcomes. Given its established clinical use, TFP emerges as a promising candidate for therapeutic repurposing in AIS.

Tropomyosin receptor kinases family members TrkA, TrkB, and TrkC mediate critical processes, such as neuronal growth, survival, and synaptic plasticity, and have been implicated in neuropsychiatric disorders. In this work, we characterized the pharmacokinetics of the novel positron emission tomography (PET) radioligand [¹⁸F]TRACK for in vivo quantification of TrkB/C in the human brain. Seven healthy volunteers (three men; 20–61 years) underwent a 90 min PET scan following an intravenous bolus injection of [¹⁸F]TRACK. Arterial blood sampling was performed throughout image acquisition. [¹⁸F]TRACK was slowly metabolized, accounting for 60% of the plasma activity at 90 min, with two more polar radiometabolites observed. Regional time-activity curves (TACs) showed moderate uptake (SUV: 1–2) and good reversibility in gray matter regions. Across regions, the two-tissue compartment model (2TCM) yielded superior fits than the 1TCM for 98% of extra-striatal gray-matter TACs, whereas it improved fits for only 52% of striatal TACs. Total distribution volume (V_T) ranged from 2.49 ± 0.30 ml/cm³ (thalamus) to 1.94 ± 0.21 ml/cm³ (hippocampus) showing good identifiability (%SE: 1%–5%) and low inter-subject variability (%CoV <14%). Transient equilibrium between [¹⁸F]TRACK in tissue and plasma was reached at approximately 70 min. Shortening the scan duration to 60 min preserved V_T accuracy and precision.

Ischemic stroke triggers a profound inflammatory response that exacerbates secondary brain injury, with infiltrating macrophages serving as major pathological mediators. Although previous studies have largely focused on immune cell–intrinsic mechanisms, the immunomodulatory role of cerebral endothelial cells in post-stroke inflammation remains poorly understood. In the current study, using single-cell RNA sequencing, we identified extensive inflammatory reprogramming in cerebral endothelial cells after stroke and discovered atypical chemokine receptor 1 (ACKR1) as a prominently upregulated regulator associated with chemokine sequestration and leukocyte recruitment. To determine its functional significance, we selectively overexpressed ACKR1 in cerebral endothelial cells using endothelial-targeted AAV-X1.1 in a mouse model of ischemic stroke. At 1 day after transient middle cerebral artery occlusion, endothelial ACKR1 overexpression preserved blood–brain barrier integrity, evidenced by maintained ZO-1 continuity, enhanced pericyte and astrocytic endfoot coverage, and reduced leakage of both exogenous tracers and endogenous IgG. By day 3, ACKR1 overexpression markedly reduced macrophage infiltration, decreased infarct volume, and improved neurological outcomes. These protective effects persisted through day 28, accompanied by improved sensorimotor recovery and attenuated brain atrophy. Collectively, our findings identify cerebral endothelial cells as active regulators of post-stroke neuroinflammation and reveal endothelial ACKR1 signaling as a potential therapeutic strategy for ischemic stroke.